tbuckley/cabot-search huggingface dataset:
Disparities in PI3K/mTOR inhibitor use, toxicities, and outcomes among patients with metastatic breast cancer.
Authors: Claire Sathe, Melissa Kate Accordino, David DeStephano, Mansi Shah, Jason Dennis Wright, Dawn L. Hershman
Journal: Journal of Clinical Oncology (2023)

6597 Background: Advances in breast cancer treatment have led to improvements in survival among patients with metastatic breast cancer (MBC). Nevertheless, Black patients and patients with lower socioeconomic status (SES) continue to bear a disproportionate mortality burden. Furthermore, because landmark trials for novel anticancer agents lacked racial diversity, their toxicity profile for minority patients remains uncertain. Our study examines the impact of race and other sociodemographic characteristics in the use and toxicity outcomes of PI3K and mTOR inhibitors (PI3K/mTORi). Methods: We conducted a retrospective analysis of EHR-derived data from the Flatiron Health Database (FHD). A dataset was constructed to include patients with hormone receptor-positive, HER2-negative MBC diagnosed between 1/1/2011 and 1/31/2022. Outcomes included PI3K/mTORi use, rates of hyperglycemia and dose reduction, and time on treatment. Multivariable logistic regression was used to evaluate factors associated with use and outcomes. Results: A total of 13,388 patients with MBC were included in our analysis, of which 2,620 (19.6%) received PI3K/mTORi (78.3% everolimus, 14.7% alpelisib, 6.9% both agents). Overall, 67.5% of all patients were categorized as White, 9.8% as Black/African-American (Black/AA); 18.9% were &gt;75 years old; 10.1% were treated at an academic site; 4.0% had Medicaid insurance. Insurance through Medicaid was associated with lower use of PI3K/mTORi compared to commercial insurance (15.6% vs 18.8%; OR: 0.76, 95% CI: 0.59-0.99, p=0.04), as was advanced age (10.9% for &gt;75 years old vs 22.9% for &lt;60 years old; OR: 0.68, 95% CI: 0.58-0.80, p&lt;0.001) and poorer performance status at diagnosis (15.1% for ECOG ≥2+ vs 22.9% for ECOG 0; OR: 0.84, CI: 0.72-0.98, p=0.03). Odds of PI3K/mTORi use were almost 50% higher for patients treated at an academic center (OR: 1.46, CI: 1.06-2.05, p=0.02). While Black/AA patient had lower rates of use than White patients (17.4% vs 20.1%), they had similar odds of receiving PI3K/mTORi on multivariable analysis (OR: 1.00, CI: 0.85-1.17, p&gt;0.9). Black/AA patients experienced higher rates of hyperglycemia on PI3K/mTORi than White patients (67.6% vs 52.5%). On multivariable analysis, odds of hyperglycemia were twice as high for Black/AA patients (OR: 2.1, CI: 1.33-3.35, p&lt;0.01). However, rates of dose reductions and time on PI3K/mTORi therapy did not differ significantly among White vs Black/AA patients. Conclusions: This analysis of real-world data suggests that lower SES is associated with decreased PI3K/mTORi use. Efforts to improve access to these life-prolonging agents are warranted. Of concern, we also found racial disparities in toxicity outcomes, with Black patients having twice the risk of hyperglycemia. Greater attention to the tolerability of novel agents in diverse populations is warranted.
Identification of healthcare vulnerabilities associated with unplanned hospital care in Black patients with pancreas cancer.
Authors: Kristen M John, Tanya C. Louis, Deepak Saluja, Daniel King
Journal: Journal of Clinical Oncology (2023)

e18572 Background: Black patients with pancreatic cancer are underrepresented in clinical trials and have worse outcomes than other patients. A retrospective analysis we conducted of 658 patients with pancreatic cancer identified that Black patients are 2.8x more likely to have recurrent ED visits than non-Black patients. This finding motivated this study of Black patients with pancreas cancer who had ED visits over a two-month period to better understand the causal factors that predispose this population to higher rates of unplanned hospital care. Methods: A quality improvement pilot study of Black patients with pancreas cancer who had ED visits between 12/06/22-02/06/23 was conducted. Computational identification of this cohort was performed using a novel Power BI dashboard that tracks health system encounters by patients with pancreas cancer using ICD10 C25 as a cohort identifier in daily updates. Each ED visit then prompted a phone call to the patient from an African American oncology nurse practitioner who served as a cultural translator to evaluate their healthcare vulnerabilities. Demographic and clinical features were recorded from the EMR. Median household income was extrapolated by zip code using data from the US Census Bureau. Results: During this two-month period, 14 Black patients had at least 1 ED visit. Of these, 50% had ≥2 ED visits during this timeframe. Through retrospective review, we found that patients in this cohort had an average of 4.4 ED visits in the past year. The cohort was 50% male with a mean age of 65.5 years and median household income of $67,032. 21% have commercial insurance, 36% have Medicaid, and 43% have Medicare. 86% established care with a primary care physician and 71% established care with a medical oncologist. 79% of patients did not have a social work assessment in their charts. We were unable to reach 50% of patients in this cohort at their preferred phone numbers. Of the patients we connected with: 71% note their highest level of education as high school, 29% do not feel safe in their communities, 14% lack a reliable support system, and 57% experience financial insecurity. Conclusions: We observed a substantial burden of ED visits among Black patients. Remarkably, half of the patients already required a second ED visit during the two-month span of this project. Given these intriguing results, we intend to pursue a prospective study using a validated questionnaire to better understand and address the factors that lead to these ED visits.
Genomic characterization of vulvar squamous cell carcinoma to reveal differential gene expression based on clinical outcome.
Authors: Mary E. Gordinier, Geoffrey Schau, Shanna Brotzge Pollock, Lisa Shields, Sameer S. Talwalkar
Journal: Journal of Clinical Oncology (2023)

e17633 Background: The greatest challenge in the management of vulvar squamous cell carcinoma (VSCC) is treatment of recurrent disease where options for surgery and radiation have been exhausted, or treatment of disease where distant metastasis is present. Identification of mutations differentially expressed between tumor from patients who died of aggressive disease and tumor from patients with an indolent course could reveal novel prognostic indicators and guide development of therapeutic drugs. Methods: From 202 consecutive patients with VSCC, patients who recurred and died of disease (group A) were identified and matched by age, tumor size, depth of invasion and nodal status with those whose disease did not recur (group B). Tumor and matched normal samples from 21 patients were assayed by a broad NGS panel covering 648 genes, including whole exome and transcriptome sequencing. Immunohistochemistry (IHC) for PD-L1 (22C3) and p16 was also performed. Results: Whole transcriptome data revealed 6 genes that were strongly differentially expressed between the aggressive and indolent groups: ACVR2A, TGM3, ROS1, NFEL2, CCND1 and BCL6. Biologically relevant DNA mutations were significantly greater in the aggressive cohort versus the indolent cohort: 7 vs 2.3 mutations per patient. The most common genomic alterations were mutations in TP53 and the promoter region of TERT. TP53 alterations occurred almost exclusively in group A. Other common genomic events include alterations of FAT1, CDKN2A, PIK3CA, CCND1, and LRP1B. All samples were MSI stable, and tumor mutational burden was similar in groups A and B. Most VSCC specimens (81%) were positive for PD-L1. Conclusions: We report that TGM3 and ACVR2A genes are significantly under-expressed in tumors with poor outcome. Further investigation into the silencing of these genes may advance knowledge of the pathogenesis of VSCC and potentially yield therapeutic targets. Clinical outcome of VSCC appears independent of MSI, TMB or PD-L1 status. [Table: see text]
Ombipepimut dosing emulsion (ODE) + bevacizumab (bev) vs bev alone in patients (pts) with recurrent or progressive glioblastoma (rGBM).
Authors: Samuel Aaron Goldlust, Jong Hee Chang, Yoshitaka Narita, Mary Roberta Welch, Richard M. Green, Jan Drappatz, David Eric Piccioni, Yu Jung Kim, Jason M. Melear, Shota Tanaka, Kuo-Chen Wei, Karen L. Fink, Marshall W. Pitz, Timothy Francis Cloughesy, John Frederick de Groot, Nanci McClellan, Matthew Hitron, Bo Xu, Bo Jin, Claudia Lebedinsky
Journal: Journal of Clinical Oncology (2023)

2022 Background: ODE is an investigational cancer vaccine derived from Wilms tumor 1. WIZARD was a randomized, adaptive, phase 3 study to test ODE + bev vs bev in rGBM pts (NCT03149003). Patients were stratified prior to randomization based upon KPS [60 or 70] vs [80 to 100] and extent of resection at initial diagnosis. Patients with low KPS (e.g., 60) are generally underrepresented in clinical trials. Methods: Pts ≥18 years with GBM at first recurrence were enrolled. Overall survival (OS) was the primary endpoint; the key secondary endpoint was the 12-month OS rate. The primary and the key secondary endpoints were tested using 1-sided test with an overall significance level 2.5%. The Lan-DeMets error spending function based upon O’Brien-Fleming stopping boundaries was used to adjust the significance level for the interim and final analyses. Results: From April 2018 to Aug 2021, 217 pts were randomized 1:1; 109 to ODE + bev and 108 to bev. OS was analyzed after 185 events with a median follow-up of 31.8 months (mo). Pts at baseline had a median age of 60 years, 45.2% reported corticosteroid use, 29% had KPS 60 or 70, 7.8% had tumors that harbored IDH1 or 2 mutations, and the median tumor volume was 10,532 mm3. Baseline characteristics between treatment arms were balanced in the ITT and KPS subgroups. Pts with KPS 60 or 70 had more corticosteroid use, worse NANO scores, and larger tumor burden than those with KPS 80-100. The study did not meet its primary endpoint of OS by ITT (ODE + bev: 10.2 mo vs bev: 9.4 mo, 1-sided p-value: 0.2159). Pts with KPS 60 or 70 had longer OS when treated with ODE + bev (8.2 vs 6.3 mo, 45% death risk reduction, 1-side p value: 0.0119). Grade 1 or 2 injection site reaction was the most common TEAE in the ODE + bev arm. No clinically significant difference in safety was noted between KPS subgroups. Conclusions: The data in pts with KPS 60 or 70 suggested benefit with ODE + bev that was consistent across different endpoints and that warrants further validation. Clinical trial information: NCT03149003 . [Table: see text]
Adding mitomycin (MM) to bacillus Calmette-Guérin (BCG) as adjuvant intravesical therapy for high-risk, non–muscle-invasive urothelial bladder cancer (NMIBC): BCGMM; ANZUP 1301.
Authors: Dickon Hayne, Martin R. Stockler, Andrew James Martin, Steve P McCombie, Danka Sinikovic Zebic, Patricia A. Bastick, Emma Kate Beardsley, Mark Frydenberg, William Green, Jeremy Grummet, Cynthia Hawks, Joseph Ischia, Andrew Mitterdorfer, Manish Patel, Matthew Roberts, Shomik Sengupta, Ratnesh Kumar Srivastav, Andrew David Redfern, Ian D. Davis
Journal: Journal of Clinical Oncology (2023)

TPS4617 Background: Adjuvant intravesical BCG decreases disease recurrence and progression in high-risk, NMIBC, however recurrence occurs in 30% of those affected, despite optimal therapy. Meta-analyses evaluating addition of intravesical MM to BCG showed lower rates of recurrence and cancer-specific mortality in people with NMIBC who received combination regimens. Phase 3 randomized trials to definitively test this combination are lacking. The BCGMM trial (NCT02948543) will determine the effects of adding MM to the standard BCG after resection of high-risk NMBIC. This is the largest study evaluating this approach in high-risk NMIBC, is of particular relevance given the current BCG shortage, and has the potential to change global practice. Methods: This open-label phase 3 trial is randomizing 500 participants stratified by stage, site of disease, and presence of carcinoma in-situ, in a 1:1 ratio to Arm A (BCG induction weekly x6 then monthly x10) or Arm B (BCG weeks 1, 2, 4, 5, 7, 8; months 4, 5, 7, 8 + MM weeks 3, 6, 9; months 3, 6, 9, see figure below). This provides 85% power to detect an absolute improvement of 10% in 2-year disease free survival (DFS) at 2p = 0.05. Stage 1 (n = 130) was to determine rates of treatment completion, activity reflected by cystoscopic findings at 3 months, adverse events, resource use, and health related quality of life, established feasibility. Stage 2, including an additional 370 participants, will provide information on DFS, time to recurrence and progression, overall survival, and identification of potential predictive biomarkers, is estimated to complete accrual by Q2 2023. Progress As of Jan 2023, 484 of 500 planned participants have been recruited from 16 Australian and 1 UK site. In stage 1, successful treatment completion, defined as 75% or more of planned treatment doses, was achieved by 76% in the experimental group (BCGMM) versus 60% in the control group (BCG alone). Clinical trial information: NCT02948543 .
Single cell analysis to study the longitudinal changes in systemic tumor immune environment in cervical cancer after radiochemotherapy.
Authors: Caining Zhao, Zhiyuan Xu, Yan Zhang, Bin Ye, Danyang Zheng, Hao Yu, Feng-Ming Spring Kong
Journal: Journal of Clinical Oncology (2023)

e17530 Background: Chemoradiation is the mainstay treatment for cervical cancer, which affects not only tumor immune microenvironment (TIME) but may also the systemic tumor immune microenvironment (STIE). Improved understanding of STIE beyond the tumor may enhance improving treatment strategies for cervical cancer. With these motivations, we applied single-cell RNA-sequencing (SCRNA-seq) to investigate longitudinal dynamics of a comprehensive set of immune cells in cervical cancer patients receiving chemoradiation (RCT). Methods: Two patients diagnosed with cervical squamous cell carcinoma at a locally advanced stage and received 45Gy/25f, with concurrent cisplatin, were enrolled. Peripheral blood was collected for SCRNA-seq using the 10× Genomics. Fresh blood samples were obtained at baseline 1-week, 2-week, 3-week, 5-week (end of external beam radiotherapy) and after Chemoradiation. Seurat 4.0 was used to cluster and annotate cell clusters. Results: A total of 90862 cells were clustered into 3 main subsets, including NK&amp;T, B, and myeloid subsets. Then NK&amp;T subset was extracted and further annotated into 10 clusters, including CD8+T naive, CD8+T effector, CD8+T effector memory, mucosal-associated invariant T (MAIT), cycling CD8+T, CD4Tem, CD4+T naive/central memory, regulatory T (Treg), natural killer (NK), and NKT cells. After plotting the dynamic changes of different cell types, MAIT and cycling CD8+T cell steadily increased with time or RT dose accumulation, suggesting that RCT could induce their proliferation. MAIT highly expressed CD69 and CXCR4 much like CD8+T effector memory cell, and cycling CD8+T cell expressed CX3CR1 like CD8+T effector cell. Besides, pseudotime analysis revealed that the differentiation process started from naive CD8+T cell towards cycling CD8+T cell passing through effector memory CD8+T cell, and effector CD8+T cell. In this process, the transcriptionally distinct MAIT cell belong to a different branch of the Pseudotime trajectory compared to the rest of the T cells, albeit mapping close to effector memory CD8+T cell, in line with their shared phenotypic identity. Enrichment was employed to explore their function and MAIT was enriched with genes involving cytokine-cytokine receptor interaction. Moreover, MAIT cell with increased antigen process and presentation function was note, and PD-1 checkpoint pathway was up-regulated during RCT. Conclusions: Chemoradiation induced the accumulation of MAIT cell which has increased antigen process and presentation features and cycling CD8+T cell with a higher PD-1 checkpoint pathway gene expression signature. Taken together, we provide insight into the peripheral immune remodeling induced by RCT, which will help optimize and improve treatment strategies for cervical cancer. Clinical trial information: NCT05061342 .
Defining the patient population with HER2-low breast cancer in Hawaii.
Authors: Amanda Yachiyo Beaman, Sara Hayama, Ian Pagano, Jeffrey Killeen, Jami Aya Fukui
Journal: Journal of Clinical Oncology (2023)

e18560 Background: About half of HER2-negative tumors (immunohistochemistry (IHC) 0, IHC 1+, or IHC 2+ without in-situ hybridization (ISH) amplification) are HER2-low (IHC 1+ or IHC2+ without ISH amplification). These tumors have gained attention due to their responsiveness to HER2-directed antibody-drug conjugates. Most studies have found a positive association between HER2-low and hormone receptor (HR) expression. Few studies report the demographics of patients that develop HER2-low tumors, and those that do were performed in ethnically homogeneous populations. Our study aims to characterize patients with HER2-low tumors in Hawaii, the US state with the highest diversity index, to better understand the patient population affected by HER2-low tumors. Methods: A retrospective chart review at a major health system in Hawaii evaluated all breast cancer specimens with HER2 testing performed between January 2021 and June 2022. Patient demographics at the time of diagnosis were collected, including age, menopausal status, body mass index (BMI), race/ethnicity. Tumor characteristics were identified by searching pathology reports and included: HER2 status-IHC score and ISH amplification, HR status, histologic type and grade, clinical stage, and 21-gene recurrence score. Results: Clinical and pathologic data was available for 332 cases of HER2-low breast cancers out of 1,478 cases. Of these, 309 (93.1%) were HR+, and 23 (6.9%) were HR-. In the HER2-low, HR+ group 53 (17.2%) were age &lt; 50 and 256 (82.8%) were age 50+, compared to the HER2-low, HR- group with 2 (8.7%) patients and 21 (91.3%) patients respectively. Of all patients with HER2-low tumors, 99 (29.8%) were Japanese, 64 (19.3%) were White, 60 (18.1%) were Filipino, and 47 (14.2%) were Native Hawaiian. This distribution remained constant irrespective of HR status. Those with a BMI of &lt; 25 kg/m 2 made up 39.7% of HER2-low patients, and those with a BMI &gt; 25 kg/m 2 made up 54%. Of 159 HR+ cases that had a 21-gene recurrence score, 133 (83.7%) of these had a low score (£25). Most HER-2 low tumors were &lt; 2cm, grade 1 or 2, and stage 1A. Conclusions: Our data confirmed the strong relationship between HER2-low and HR+ expression. As expected, most patients were age 50+, although there were more patients younger than 50 in the HER2-low, HR+ group compared to the HR- group. The ethnic distribution of HER2-low tumors is consistent with that of the general population of Hawaii, there does not appear to be any group more at risk than another. [Table: see text]
Pelabresib (CPI-0610) monotherapy in high-risk essential thrombocythemia refractory or intolerant to hydroxyurea: Preliminary results from MANIFEST study.
Authors: Francesco Passamonti, Andrea Patriarca, Steven Knapper, Candido Rivera, Joseph Scandura, Timothy Devos, Nikki Granacher, Adam J. Mead, Stephen Oh, Jeanne M. Palmer, Raajit Rampal, Lino Teichmann, Jie Cui, Sandra Klein, Gozde Colak, Claire Harrison
Journal: Journal of Clinical Oncology (2023)

7019 Background: High-risk essential thrombocythemia (HR ET) is characterized by thrombocytosis, thrombohemorrhagic events and systemic symptoms. Pts can experience intolerance, inadequate response or loss of response to first-line cytoreductive therapies (hydroxyurea [HU] or interferon alfa-2a). BET protein inhibition is a novel therapeutic strategy that downregulates inflammatory cytokines and may inhibit differentiation and proliferation of abnormal megakaryocytes involved in ET pathogenesis. Results from the Phase 2 MANIFEST study (NCT02158858) suggested potentially encouraging clinical efficacy in pts with myelofibrosis treated with Pelabresib (PELA), an oral, small-molecule, investigational BET inhibitor. Here we present preliminary results from MANIFEST Arm 4 investigating PELA monotherapy in HR ET refractory or intolerant to HU. Methods: Eligible pts had platelets &gt; 600 x 10 9 /L and ≥ 2 symptoms (average score ≥3/ TSS≥15). Pts received PELA monotherapy 225 mg QD. The primary endpoint was complete hematologic response (CHR; normalization of platelet count (≤400 x 10 9 /L), WBC count (≤10 x 10 9 /L) confirmed after one cycle [after 3 weeks]) and normal spleen size. Secondary endpoints included partial HR (PHR; platelets 400–600 x 10 9 /L and WBC ≤10 x 10 9 /L), symptom improvement (≥50% TSS reduction) and safety. Results: As of July 2022, 20 pts with HR ET were treated: median age 64 yrs (42–83), median Hgb 13 (10–16) g/dL, median platelet count 772 (418–1255) x 10 9 /L and median TSS 32.7 (6.9–123). The majority of pts had a hematologic response (90% [18/20] unconfirmed CHR or PHR); confirmed CHR was observed in 40% (8/20) (Table). Median platelet and WBC count at Wk 12 was 446 x10 9 /L and 8.2 x 10 9 /L, respectively. TSS reduction was reported in 86% (12/14 pts); median TSS reduction at Wk 12 was –31%. Hgb levels remained stable through Wk 24. The most common nonhematologic AEs were nausea (60%; 10% Gr 3), diarrhea (35%; 5% Gr 3) and dysgeusia (35%; no Gr 3). Hemorrhagic or thromboembolic events were reported in 30% pts (15% Gr 3). No events of thrombocytopenia and no Gr 4 events or higher were reported. Conclusions: Preliminary results from Arm 4 of the MANIFEST study suggest potential clinical benefit with PELA monotherapy in pts with HR ET refractory or intolerant to HU as supported by hematologic responses and symptom improvement. Safety results are consistent with the known safety profile of PELA and as expected in the underlying study population. Clinical trial information: NCT02158858 . [Table: see text]